PB1876: ACALABRUTINIB RELATED INFECTIOUS COMPLICATIONS-A SYSTEMATIC REVIEW AND META-ANALYSIS OF PHASE III RCT
Authors: K. Parmar, K. Thein, L. Tijani, S. Ball
Journal: HemaSphere (2022)

Background: Acalabrutinib is a new, selective, irreversible Bruton's tyrosine kinase inhibitor (BTKi) approved for the treatment of adults with chronic lymphocytic leukemia (CLL). It has shown remarkable efficacy and significantly improved toxicity profile than ibrutinib (a first generation BTKi) in clinical studies. Patients with CLL have inherent immunodeficiency due to disease associated defects in innate and adaptive immunity. Although ibrutinib leads to an immune reconstitution, reports have suggested an increased risk of infections (particularly fungal) with ibrutinib in patients with B cell malignancies. However, the risk of infection with acalabrutinib is unknown in patients with CLL. Aims: We conducted this systematic review and meta-analysis to estimate the risk of infections associated with acalabrutinib in patients with CLL. Methods: A comprehensive literature search was performed in PubMed, EMBASE, Clinical trials.gov and meeting abstracts till January 31,2021. All randomized controlled trials comparing acalabrutinib-based regimens with a control group in patients with CLL, with infections reported as adverse effects were included. Pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated using the Mantel-Haenszel method of the fixed-effect model. Heterogeneity of effect size was quantified using the I2 statistic. Statistical analysis was performed using the Review Manager, version 5.3. Results: Three phase III RCT with total of 1362 patients were included for our analysis (Figure). Byrd et al., compared acalabrutinib with ibrutinib. The ASCEND trial compared acalabrutinib with investigator's choice chemotherapy, either idelalisib plus rituximab or bendamustine plus rituximab. In the ELEVATE -TN study the comparator arm included the combination of chlorambucil and obinutuzumab. Acalabrutinib was used at the dose of 100mg twice daily in all 3 studies. All but ELEVATE -TN study included patients previously treated with CLL. The upper respiratory tract infection (URTI) was the most reported type of infection across trials. The risk of total infection (CTCAE any grade) was significantly lower (pooled RR 0.92; 95%CI 0.85-0.99; P=0.03) in patients on acalabrutinib containing regimens; however, there was no difference between CTCAE grade 3+ infections between the two groups (Figure). On further analysis of types of infections, patients on acalabrutinib had a significantly less URTI than those in the control arm (pooled RR 0.76; 95% CI 0.61-0.96; P=0.02) (Figure). There was no difference in grade 3+ URTI, pneumonia (any grade), grade 3 pneumonia or sepsis between the two groups. Looking at infectious etiologies, patients on acalabrutinib containing regimen did not have an increased risk of fungal (pooled RR 0.76; 95% CI 0.32-1.81; P=0.53) or viral infections than other regimens. The rate of treatment discontinuation due to infections in the acalabrutinib group was significantly less compared to control (pooled RR 0.53; 95% CI 0.33-0.87; P=0.01). We noted a substantial heterogeneity across trials included in our analysis. Image:Summary/Conclusion: Our meta-analysis demonstrated that patients on acalabrutinib-containing regimens experienced a significantly lower relative risk of infections compared to non-acalabrutinib-based therapies. There were significantly lower risks of URTI and infection related treatment discontinuations with acalabrutinib therapy in patients with CLL.